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Corresponding author: Kerry J. Ressler; Email: kressle@emory.edu

Author contributions: R.A. and K.J.R. conceived and designed the study.

R.A. performed the behavioral experiments in mice, systemically injected SR-8993, and analyzed the data.

R.A. performed the micropunches and the mRNA isolation.

R.A. analyzed the microarray.

R.A. analyzed and performed the qPCR experiments.

R.A. performed stereotactic surgeries, intra-amygdala infusion of SR-8993, and histological experiments.

Y.T.C. and T.D.B. synthesized SR-8993.

M.C. performed and analyzed the pharmacokinetic experiments.

S.P.B. and H.S.-U. performed mouse behavior studies.

J.S.S. and T.J. performed and analyzed the fMRI experiments.

L.A. obtained the PSS data, and L.A. and K.J.R. analyzed the PSS data.

L.A. performed the genome-wide association studies, and L.A. and K.J.R. analyzed the data.

T.J. performed the FPS and analyzed the data.

K.J.R., S.P.B., T.J., T.D.B., B.B., E.B.B., and C.W. obtained the funding.

R.A. and K.J.R. wrote the manuscript.

We appreciate the technical assistance of G. Doho (Emory Cancer Genomics Shared Resource) with the microarray analyses.

We also thank M. Dierssen and A. Regi for sharing the software jTracks, which was used to analyze the water maze.

Competing interests: S.P.B., Y.T.C., H.S.-U., T.D.B., and C.W. have filed a patent related to this work: Provisional Patent Application Serial No. 61804316 “Substituted benzimidazoles as nociceptin receptor modulators” docket # 1361.184PV2.

The other authors declare that they have no competing interests.

Subjects:

Research Funding:

This work was supported by NIH grants MH071537 (K.J.R.), MH096764 (K.J.R.), MH092576 (T.J.), and MH098212 (T.J.) as well as Brain and Behavior Research Foundation, the Burroughs Wellcome Fund, and Emory Medical Care Foundation (T.J.).

Support was received from the NIH/National Center for Research Resources base grant P51RR000165 to Yerkes National Primate Research Center.

The chemistry/new compound work was supported by the National Institute on Alcohol Abuse and Alcoholism (AA017943 to C.W., AA018665 to M.C.), the National Institute on Drug Abuse (DA035055 to C.W. and S.P.B., DA035056 to T.D.B.), and the National Center for Advancing Translational Sciences (UL1TR000454).

Amygdala-Dependent Fear Is Regulated by Oprl1 in Mice and Humans with PTSD

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Journal Title:

Science Translational Medicine

Volume:

Volume 5, Number 188

Publisher:

, Pages 188ra73-188ra73

Type of Work:

Article | Post-print: After Peer Review

Abstract:

The amygdala-dependent molecular mechanisms driving the onset and persistence of posttraumatic stress disorder (PTSD) are poorly understood. Recent observational studies have suggested that opioid analgesia in the aftermath of trauma may decrease the development of PTSD. Using a mouse model of dysregulated fear, we found altered expression within the amygdala of the Oprl1 gene (opioid receptor–like 1), which encodes the amygdala nociceptin (NOP)/orphanin FQ receptor (NOP-R). Systemic and central amygdala infusion of SR-8993, a new highly selective NOP-R agonist, impaired fear memory consolidation. In humans, a single-nucleotide polymorphism (SNP) within OPRL1 is associated with a self-reported history of childhood trauma and PTSD symptoms (n = 1847) after a traumatic event. This SNP is also associated with physiological startle measures of fear discrimination and magnetic resonance imaging analysis of amygdala-insula functional connectivity. Together, these data suggest that Oprl1 is associated with amygdala function, fear processing, and PTSD symptoms. Further, our data suggest that activation of the Oprl1/NOP receptor may interfere with fear memory consolidation, with implications for prevention of PTSD after a traumatic event.

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© 2013 by the American Association for the Advancement of Science; all rights reserved.

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